title: Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.
abstract: GH secretion and release are complex phenomena depending on activation of several genes, including those encoding GH, GHRH, and its receptor (GHRH-R). The GH gene, which is the most extensively analyzed sequence in patients with familial GH deficiency (GHD), represents the main known target of mutations. To test the involvement of the GHRH-R gene in this disease phenotype, we investigated one candidate Tamoulean family originating from Sri Lanka. Two brothers, with extremely short stature (< -4 SD) and no dysmorphy, were diagnosed as having complete GHD, unresponsive to exogenous GHRH and associated with PRL levels within the lower normal range. Magnetic resonance imaging examination showed anterior pituitary hypoplasia with a normal pituitary stalk. Both patients increased their growth rate while under GH therapy. Molecular investigations revealed a homozygous GHRH-R gene mutation that introduces a stop codon at residue 72. This mutation, which predicts a severely truncated receptor lacking the seven membrane spanning domains, is identical to that recently reported in one Indian Moslem family, raising the possibility of a founder effect. There was no clear evidence for height reduction in the three heterozygous individuals studied. This observation, which underlines the phenotypic criteria associated with a loss of GHRH-R function, raises the question of the frequency of GHRH-R abnormalities among GHD patients.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 468, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: I
authors.initials: I
authors.lastname: Netchine
authors.forename: P
authors.initials: P
authors.lastname: Talon
authors.forename: F
authors.initials: F
authors.lastname: Dastot
authors.forename: F
authors.initials: F
authors.lastname: Vitaux
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: S
authors.initials: S
authors.lastname: Amselem
mesh_terms: D002648:Child; D013007:Growth Hormone-Releasing Hormone; D019382:Human Growth Hormone / Q000172:deficiency* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010903:Pituitary Gland, Anterior / Q000473:pathology; D016133:Polymerase Chain Reaction; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D013188:Sri Lanka
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; C048250:somatotropin releasing hormone receptor